CF Flashcards
How has the demographic of CF pts changed overtime?
Used to be a disease of only children, now we see adults also being affected.
What is the inheritance pattern of CF?
What is the carrier status in the UK?
Autosomal recessive - 2 faulty copies required to present with CF
Carrier rate: 1 in 24 carriers
What is the likelihood of a child being born with CF in the UK?
1/24 x 1/24 x 1/4 = 1 in 2500 births in UK
(likelihood of two adult carriers meeting and that child having CF).
How many people are affected with CF worldwide?
70, 000
What are the likely offspring of two carriers?
1 child affected
2 unaffected carriers
1 unaffected non carrier
What is the protein affected in cf?
Describe this protein
CFTR - cystis fibrosis transmembrane conductance regulator (chloride channel)
2 nucelotide binding domains that go through the cell wall and an R domain –> forms a gate with a regulatory domain at the bottom that opens and closes
What class of protein does the CFTR channel belong to?
What does it allow to move into the cell?
ATP driven transmembrane conductance regulator
regualtory domain moves
allows negatively charged Cl- ions through the cell wall
Also plays a role in Na+ transport, Cl- moves, Na+ follows
What occurs to the CFTR to cause CF?
what is the overall effect of this?
mutation within DNA –> protein w error
CFTR = complex protein; ER normally ensures correct protein folding, packaged into vesicle and is sent to the cell wall
Misfolded protein –> does not get transported to cell wall
Lack of transport to cell wall, no Cl- transported out the cell, dry sticky mucus an epithelial cell membrane
Thick secretions; harbours pathogens
What are the complications of CF?
Obstructive lung disease
harbouring of pathogen
infection
inflammation
causes lung damage
leads to respiratory failure
What is the principle of tx in CF?
Early intervention
prevention of lung damage
disease modification
How do you diagnose CF?
- Newborn screening (UK only) –> Heel prick test
What are the conditions screened for in the UK via heel prick test?
CF
congenital hypothyroidism
sickle cell disease
phenylketonuria
medium chain acyl coa ….
What are the pro’s/ cons to screening via heel prick test?
Pros: early identification and early intervention; prevention of disease progressing, familial support given early
Cons: missed individuals falsely reassured, not preventing disease,
What makes a good screening test?
needs to be an important problem
needs to be a good test
needs to be some form of intervention
screening needs to actually help
needs to be able to be implemented
What is screened for in CF?
Immunoreactive trypsinogen (produced by pancreas)
How are IRT levels used to categorise CF risk?
Low IRT –> changes of CF v low
higher IRT –> look for genetic mutation –> if 2 mutations CF suspected, 1 mutation susepcted carrier, no mutation CF not suspected
What is a second test used to diagnose CF?
Chloride sweat test
How does the CF sweat test work?
Epithelial cells with CFTR channel also found in sweat duct
CFTR channel brings NaCl back into the cell, in CF the channel cannot do so and NaCl sits on the skin
CF will have elevated concentrations of sweat chloride; normally this is very low.
What is the effect of screening?
Child with median age of survival against 1940 –> median survival only 1 yrs
2007 heel prick test came in nationally, see median age of survival move up into 30 yrs
medical definition of disease
medical definition of illness?
Disease –> alteration in biological structure or functioning
Illness –> experience defined, the innately human experience of suffering
What are the sx of CF in newborn?
What are the sx of CF in older children?
Newborn:
loose fatty stools (due to lack of absorotion of fats, lack of pancreatic enzyme)
repeated chest infection
productive cough
failure to thrive/ slow growth
bowel obstruction (meconium ileus presents in 1/5 babies)
Older child:
chronic sinusitis
nasal polpys
pancreatitis
constipation
recurrent chronic pancreatitis
infertility due to congenital abscence of vas deferens or thick cervical mucus
metabolic bone disease
diabetes
liver disease
What are the different severities of CF mutation?
class 1 stops protein being produced at all –> no fucnction
class 2 –> misfolded protein –> does not transport to cell membrane –> no function
class 3 –> gets to cell membrane but problem with regualtory domain, does not allow conductance
class 4 –> conductance problem, Cl- movement is slower .
Class 5 –> turnover mutation; working protein but not enough of it
What is the timeline of CF pathology?
Treatment approaches for CF:
Thick sticky mucus
- Thick sticky secretions –> dilute, shift the secretion
- hypertonic saline –> osmotic action; hydrates mucus
- nebuliser used 1/2 a day
- DNase (dornase alfa or pulmozyme) –> synthetic enzyme that cleaves neutrophil DNA which makes the mucus particularly viscous (after neutrophils apoptose).
Treatment approaches for CF: Obstructive lung disease
- (inhaler to dilate airway used with hyperreactive airways, potentially sensitive to saline solution )
- physiotherapy –> mechanically shift mucus by airway clearance techniques –> younger children various patting techniques; older children positive expiratory pressure helps clear out secretions
- positive pressure also delivered by device
Treatment appraoches to CF: infection and inflammation
Infection –> antibiotics, treated agressively, early and monitor
Antibiotics used to prevent, treat and to eradicate infection
Why might AB’s be given even if infection suspected to be viral?
W viral infection likely to be a high degree of inflammation within the airways anyway; leads to further airway damage and high likelihood of secondary bacterial infection occurring.
What is a bacterial infection of particular importance in CF?
Pseudomonas aeruginosa
gram negative; rod shaped
opportunisitic infection
found everywhere
What infections are common in CF?
H influenza (early infection)
B cepacia,
MRSA
S.aureus
Pseudomona aeruginosa
Why is P.aeruginosa infections particularly bad in CF?
Secretes exopolysaccarides –> protects the bacteria therefore difficult to tx in its mucoid form
fills up airway with purulent material that is difficult to clear –> leads to resp failure
How common are chronic pseudomonas infections in CF patients?
Average number of individuals per CF centre around 7% patients affected
What occurs if pseudomonas infection detected?
- Eradicate with antibiotics
- ciprofloxain and nebulised ??
- IV courses if particularly unwell; often two IV AB’s
- monitor and detect if still there
- some patients become colonised
Extra pulmonary care: nutrition
Why do CF patient’s nutrition suffer?
Nutrition is a significant multifactorial problem
lack of pancreatic enzymes, malabsorption of fats and carbohydrates lost in stools
recurrent low grade bronchial infection; chronic cough; less tolerance to illness, vomiting more
describe pathology of decreased nutrition in CF pts
- malabsorption of fat
- lack of fat soluble vitamins
- progressive pulmonary infection
- CF related diabetes
- motility of GI tract
- small bowel bacterial overgrowth
What is the energy requirement of CF pts?
110 - 200% compared to healthy population
What is PERT?
Pancreatic enzyme replacement therapy:
(pancreas can be small, necrosed even at birth in CF pt.
This is why IRT increases in those first few weeks, then drops away )
Enzymes replaced: 1) lipase 500-2500 unit per kg), protease, amylase
What is the rationale for PERT?
Give pancreatic enzymes to make use of the calories individual already has
Extra pulmonary care: increase calorie intake?
Enteral supplementation:
Supplements
NG Tube
PEG
What vitamins may be given to CF pts?
Fat solubule vitamins:
Vitamin A, D, E , K (DAKE)
What other than supplementation and vitamins is also given in CF pts?
Sodium chloride given due to excess loss of NaCl in sweat; given particularly in summer to prevenet hyponatremia.
What is DIOS?
What is it due to?
How may it present?
Distal intestinal obstruction sundrome
due to decreased motility, thick intestinal mucus.
May present with pain, altered bowel habits, distention, vomiting, mass on the abdomen. Need to distinguish between complete blockage and incomplete blockage.
What are the risks of DIOS?
Severe genotype
pancreatic insufficiency
inadequate salt intake
dehydration
history of meconium ileus
post organ transplant
How is DIOS managed?
DIOS managed with osmotic laxatives:
Movicol
gastrogaffin
klean-prep (liters of water to flush out)
Aim: to avoid surgery and clear blockage
How may meconium ileus scar
Scar over central abdomen
How does the weight of CF patients change with age?
Overall loss of weight as CF children approach teenage yrs
Due to onset of CF associated diabetes
What is the pathogenesis of diabetes in CF patients?
EDIT CARD
Direct effect on the pancreas itself
Reduction in the amount of antioxidants within the body –> beta cell loss
steroid treatments and infections pushes blood glucose up
liver disease also raises glucose
defective CFTR –> decreased alpha cell suppression –> Rise in glucagon
How can we test for diabetes in CF pts?
Given oral glucose load, measure blood sugar with time.
With adequate response, blood sugar increases and is then brought down due to sufficient insulin.
in cf pts blood sugar remains high
What is the definitive criteria for diabetes
fasting glucose > 7 mmol/l
2 hour post glucose challenge > 11.1 mmol/L
or HbA1C value of > 6.5%
definition of impaired glucose tolerance
definition of impaired fasting glucose
What is the benefit of continued glucose monitor
less chance of missing unnoticed highs with fingerstick tests
What is another complication of CF other than diabetes?
What % affected by cirrhosis/ portal HTN/ fatty liver?
Cystic fibrosis related liver disease
20-30% with cirrhosis
5-10% with portal hypertension
23-75% with fatty liver
3rd cause of death
What is the pathology of liver disease in CF patients?
inflammation of hepatocytes causes obstruction of the bile ducts
there may be focal changes at first that then progresses to cirrhosis.
What are the risks associated with development of liver disease in CF patients?
Time of diagnosis
Male
previous meconium ileus
exocrine insufficiency
clinical signs of liver disease on examination?
Ascites
clubbing
splenomegaly
hepatomegaly
palmar erythema
dupytrens contracture
jaundice
How do we monitor for liver disease in CF pts?
Clinical exam
liver enzyme measurement
PT measurement
ultrasound
biopsy
What acid is taken in CF pts to help liver function?
Ursodeoxycholic acid –> bile acid that improves bile flow
What are the small molecule drugs used in CF treatment?
CFTR modulators:
Ivacaftor
Lumacaftor
Tezacaftor
( Orkambi is ivacafotr and lumacafor together)
How do the small molecule drugs treat CF?
Ivacaftor:
Breaks up, enters cell, finds its way to CFTR protein on cell wall, opens the gate of the CFTR channel and holds gate open.
Therefore only works in patients with class 2 mutations –> only 5% of patients with CF
What does orkambi do?
Orkambi –> Ivacafotor and lumekaftor -> helps alter misfolded protein so it becomes escorted to cell membrane
Used for class 2 mutations (85% of individuals with delta F508 mutation can be treated).
